PROJECT SUMMARY Peripheral arterial disease (PAD) is characterized by lower limb arterial obstruction due to atherosclerosis. There are 8.5 million people with PAD in the U.S over the age of 40. Over the past 14 years, our multi-disciplinary team of investigators has developed several novel magnetic resonance imaging (MRI) endpoints for clinical trials for PAD patients with intermittent claudication (IC). Creatine chemical exchange saturation transfer (CrCEST) is a novel non-spectroscopic imaging method that allows measurement of creatine kinetics in a spatially localized manner at 3T that could increase the applicability of the measure and allow spatial matching to muscle perfusion. We hypothesize that CrCEST kinetics will distinguish PAD and normals in a highly reproducible manner and will correlate with PCr kinetics. Thus, Specific Aim 1 is to demonstrate that CrCEST kinetics distinguishes PAD patients from age-matched normal subjects and reproducibly measures calf muscle energetics with exercise. We will study 23 patients with PAD compared to 23 normal controls. We will also study reproducibility and examine correlation with PCr kinetics. Critical limb ischemia (CLI) presents as rest pain, ischemic ulceration, or gangrene due to the inability of resting blood flow to meet tissue metabolic demands. We plan to study CLI patients to both improve understanding of its pathophysiology and expand the reach of these novel methods beyond their application to IC. In recent years, endovascular revascularization has increased while surgery has declined and outcomes have improved. We hypothesize that catheter-based revascularization improves perfusion and energetics to a greater extent and sooner than surgical intervention. Therefore, Specific Aim 2 is to compare the effects of catheter-based and surgical revascularization on the time course of change in calf muscle perfusion and energetics in PAD. 120 patients (30 patients in each of 4 groups (IC with catheter-based or surgical revascularization, CLI with catheter-based or surgical revascularization) will be studied. Prognosis of CLI is significantly worse than IC with a combined mortality and amputation rate of 25-33% at 1 year. We hypothesize that lower calf muscle perfusion and worse energetics leads to worse outcome in CLI. Thus, Specific Aim 3 is to correlate muscle group specific perfusion and energetics with amputation- free survival in non-revascularized CLI. 65 patients with CLI that do not subsequently undergo revascularization will be studied and cuff/occlusion hyperemia measures of tissue perfusion with ASL before and 8-12 weeks after revascularization. Amputation-free survival will be tracked over 1-3 years.